The indole nucleus is a prominent structure motif found in numerous natural products and pharmaceutically active compounds. Examples of substituted indoles used in the preparation of pharmaceutical agents and as pharmaceutical agents themselves include Indomethacin, an anti-inflammatory medicine, Tropesin, an anti-inflammatory and analgesic agent, Mebhydroline, antihistaminic agent and Vinpocetine, a vasodilator agent. Other examples of indole compounds used as pharmaceutical agents those disclosed in U.S. patent application Ser. No. 10/198,384 and and U.S. provisional application 60/546,213, filed Feb. 20, 2004 the contents of which are incorporated herein by reference.
Many methods have been developed to meet the need building indole structures, among which the Fisher indolization still remains the most commonly used technique in industry. See: Indoles; Sundberg, R. J., Ed.; Academic: London, 1996; Sundberg, R. J. Pyrroles and their Benzo Derivatives: Synthesis and Applications. In Comprehensive Heterocyclic Chemistry. Notwithstanding this plethora of methodologies, regioselective formation of indoles with substitution at positions other than C-5 has proved to be challenging. The recently developed palladium-catalyzed indolization method by Larock et al (Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689; Larock, R. C.; Yum, E. K.; Refyik, M. D. J. Org. Chem. 1998, 63, 7652) has provided one approach to the aforementioned regioselectivity issue. Larock reported that the best results could be obtained by reacting substituted ortho-iodolines with an excess of a suitable internal alkyne sodium or potassium acetate or carbonate base plus 1 equivalent of either LiCi or n-Bu4NCl, and occasionally adding the ligand triphenylphosphine. Larock reported that this ligand was not essential for the palladium-catalyzed reaction. Larock also reported the use of triphenylphosphine as a ligand and did not find that it provided better indolization results.
This versatile “ligandless” heteroannulation of internal alkynes with 2-iodoanilines allows access to a variety of indoles which may not be readily available by conventional methods in terms of the degree of substitution and type of functionalization (eq. 1, Scheme 1). Replacing the iodoanilines with the corresponding 2-bromo or 2-chloro derivatives would be of significant practical and economical value from a cost and throughput perspective. However, Larock's protocol was not applicable to the indolization of acetylenes with 2-bromo or chloroanilines. The presence of iodide was postulated to have pronounced effect on the nature of the products in these alkyne insertion processes. (Larock, R. C.; Yum, E. K.; Refyik, M. D. J. Org. Chem. 1998, 63, 7652.) In addition, previous research on the reaction of ortho-palladation complexes with alkynes demonstrated the exclusive formation of multiple insertion products (eq. 2, Scheme 1). (Maassarani, F.; Pfeffer, M.; Borgne, G. L. Organometallics 1987, 6, 2029; (b) Maassarani, F.; Pfeffer, M.; Borgne, G. L., Organometallics 1987, 6, 2043; (c) Maassarani, F.; Pfeffer, M.; Spencer, J.; Wehman, E. J. Organomet. Chem. 1994, 466, 265.

There is a need in the art for conditions that are not substrate-specific and that could be used for performing palladium catalyzed indolizations on internal alkynes having a variety of substitutions at R2 and R3.